The intention invention relates to a method for the treatment of neurohumoral imbalance caused by alterations of cardiac function to prevent the development of heart failure by administering an effective amount of (R)-N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide to a mammal in need of such treatment.
Racemic N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide (I) has been described earlier as a hypotensive agent (U.S. Pat. No. 3,746,712) and as a cardiotonic agent having inotropic activity (U.S. Pat. No. 4,397,854). It has been reported that the inotropic action of racemic N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide is based on phosphodiesterase III (PDE III) enzyme inhibition (Ishimori t. et al., Arzneim.-Forsch. (1994) 44(5), 583-8). The compound (I) has an asymmetric carbon atom and may therefore exist in two stereoisomeric forms. The (R)- and (S)- enantiomers of (I) has been earlier described in Japanese patent application no. (Heisei) JP 3163050. However, biological activity data for the enantiomers has not been described.
At the moment series of inotropic compounds, e.g. milrinone, the mechanism of which is based on PDE III inhibition are in clinical trials for the treatment of heart failure. These compounds increase the contractility of the cardiac muscle by increasing the calcium current into the cardiac muscle and produce vasodilatation. The contraction in cardiac muscle is triggered by the binding of calcium in troponin. However, it is possible that the long-term application of PDE III inhibitors leads to calcium overload in the cardiac muscle which can trigger arrhythmias. Therefore, the main mechanism to increase cardiac contractility should be a mechanism which does not produce calcium overload. The enhancement of the turnover of intracellular calcium released from sarcoplasmic reticulum and the increase of calcium sensitivity of contractile proteins are such mechanisms which do not induce calcium overload.
When a patient has harmful alterations in the cardiac function, the contractility of the cardiac muscle can still be maintained through neurohumoral activation in the body, which increases the intake of calcium in the cardiac muscle. In this situation the calcium overload can trigger arrhythmias, and prolonged neurohumoral activation will accelerate the development of heart failure. Neurohumoral imbalance can be indicated, for example, by altered renin and noradrenaline concentrations in a patient""s plasma. PDE III inhibitors can not be used chronically in the treatment of neurohumoral imbalance because they further increase the intake of calcium into the cardiac muscle. However, the use of a calcium sensitizer can sufficiently increase the contractility already in normal and decreased calcium concentrations which would reduce the need of neurohumoral activation and thereby prevent the development of heart failure.
It has been now discovered that the (R)-enantiomer of N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide has a calcium sensitizing effect on troponin and that its main mechanism to increase cardiac contractility is the increase of calcium sensitivity of troponin. This was unexpected since the mechanism of rasemic compound (I) was reported to be PDE III inhibition. Thus, being a calcium sensitizer the (R)-enantiomer of N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide has a utility in the treatment of neurohumoral imbalance caused by alterations of cardiac function to prevent the development of heart failure.
The present invention relates to a method for the treatment of neurohumoral imbalance caused by alterations of cardiac function to prevent the development of heart failure by administering orally or parenterally in a solid or liquid dosage form an effective amount of (R)-enantiomer of compound (I) to a patient in need of such treatment.
The pharmaceutically active compound according to this invention is formulated into dosage forms using the principles known in the art. It is given to a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions. The composition according to the invention contains a therapeutically effective amount of the pharmaceutically active compound of the invention. The contents of the active compound is in the composition from about 0.5 to 100% per weight.
In the claimed method the compound of the invention may be administered to man in oral doses ranging from about 0.1 to 500 mg, preferably 0.5 to 10 mg, per day. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art. It is evident that suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds and other ingredients normally used in this field of technology may be also used.
The following example will further illustrate the invention.